This project has been designed to investigate the mechanisms of susceptibility to respiratory syncytial virus (RSV) infection and disease progression. RSV is the leading viral respiratory cause of hospitalization in infants and young children in the United States and in the world. The reason why some previously healthy infants develop LRI (bronchiolitis and pneumonia) while others remain asymptomatic or only develop upper respiratory tract symptoms after RSV infection is not well understood. Evidence exists that the degree of previous injury of the lung parenchyma in small infants could play a role in disease severity, as children with chronic lung disease are at high risk of RSV LRI. However, the majority of hospitalizations occur in previously healthy infants. Another potentially important factor that can cause lung injury during RSV LRI is innate immunity. The pulmonary infiltration during RSV LRI is composed overwhelmingly by neutrophils and macrophages and damage to the small airways (10-300 microns) affected by the virus could easily cause debris accumulation in the lumen, inflammation and edema of the small airways, and compromise ventilation. Further, most infants with RSV-associated wheezing do not respond to b2-bronchodilators, but may benefit from inhaled a-agonists that decrease edema/inflammation. Additionally, high levels of CXC chemokines (particularly MIP-1a, MCP-1 and IL-8) have been associated with increased RSV disease severity. [unreadable] [unreadable] A role for oxidative stress has been suggested in the pathogenesis of airway RSV infection. NF-E2-related factor 2 (Nrf2) is a key regulator of airway protection against oxidative injury, inflammation, and immune responses via antioxidant/defense gene induction. We have begun to investigate the role of Nrf2 in RSV infection and RSV-mediated injury using Nrf2-deficient (Nrf2-/-) and wild type (Nrf2+/+) mice intranasally treated with RSV or vehicle. Results support a key role oxidant stress in the pathogenesis of RSV-induced disease and the importance of Nrf2 in host defense against RSV. In parallel, we are using traditional positional cloning approaches as well as haplotype mapping to identify candidate RSV susceptibility genes in the mouse.[unreadable] [unreadable] In collaboration with Fernando Polack (Johns Hopkins) we have recruited a prospective cohort of infants and young children who were infected with RSV between June 1 2003 and May 31 2005 at five hospitals and clinic in Buenos Aires, Argentina. These infants and children have been characterized extensively for RSV-related disease phenotypes, and DNA has been extracted from all participating individuals. We are currently investigating whether polymorphisms in candidate innate immunity and antioxidant genes (based on studies described above) associate with disease severity in infected children.